tbuckley/cabot-search huggingface dataset:
Abstract 138: NIR fluorescent probes for senescence imaging via tunable in situ labeling
Authors: Zixin Chen, Yuzhao Zhang, Seyedehalaleh Anvar, Chang-hung Wu, Jun Liu, Joyce Z. Jiang, Lina Cui
Journal: Cancer Research (2022)

Abstract Cellular senescence is a mechanism by which a cell enters stable cell cycle arrest triggered by various types of stress such as telomere shortening, oxidative stress and DNA damage. It is implicated in a number of pathophysiological conditions including age-related diseases, degenerative disorders and cancer. Despite its importance, the current toolbox for studying or monitoring senescence in vivo is limited. We have developed a series of novel near-infrared (NIR) fluorescent probes that can be activated by senescence-associated β-galactosidase (SA-β-Gal) and self-immobilize onto intracellular proteins via in situ labeling. We compared the labeling efficiency of these probes in vitro and in cells and the results shows that by modulating the leaving group, we can improve the labeling efficiency of the probes and enhance their retention at the site of activation. These probes can be used for imaging of senescence developed in live cells, as well as long-term tracking of senescent cells in various animal models. Citation Format: Zixin Chen, Yuzhao Zhang, Seyedehalaleh Anvar, Chang-hung Wu, Jun Liu, Joyce Z. Jiang, Lina Cui. NIR fluorescent probes for senescence imaging via tunable in situ labeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 138.
Abstract 6378: The cross-talk between FTH1 and PYCR1 drives pancreatic cancer progression
Authors: Ji Min Park, Ching-Feng Chiu
Journal: Cancer Research (2022)

Abstract This study is designed to explore the effect of FTH1 on PDAC human pancreatic cancer cells, proline metabolism, and their crosstalk. Considering the high prevalence of pancreatic cancer with an absence of efficient therapy against PDAC, the present study may provide experimental evidence in support of the novel role of FTH1 in proline metabolism and suggest FTH1 as a potential target for PDAC patients. We further focus on the underlying molecular mechanism of how FTH1 cross-talks with PYCR1 and leads KRAS-mutated PDAC cell growth, investigating whether miRNAs regulation involves in FTH1 mediating PYCR1 expression. Taken together, our study provides a novel function of FTH1 and its cross-talk with PYCR1 may be a novel target for pancreatic cancer research and thus these findings will help us to find metabolite-based therapeutic strategies to improve KRAS-mutated PDAC. Citation Format: Ji Min Park, Ching-Feng Chiu. The cross-talk between FTH1 and PYCR1 drives pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6378.
Abstract 3110: Identification of the phosphorylation network in PDX and corresponding organoid (PDXO) models upon targeted therapy treatment using deep phosphoproteomic analysis[MB1]
Authors: Xiaoxi Xu, Marco Tognetti, Yuehan Feng, Limei Shang, Leilei Chen, Jessie Wang, Roland Bruderer, Ludovic Bourré, Henry Li
Journal: Cancer Research (2022)

Abstract In precision medicine, genomic, transcriptomic, and proteomic data has contributed to the identification of novel driver genes and the molecular-level characterization of cancers. This data has led to a better understanding of drug modulation and resistance mechanisms. Patient-derived tumor models, including patient-derived xenograft (PDX) and organoid counterparts (PDXO), have been increasingly viewed as predictive preclinical cancer models. These models closely recapitulate tumor complexity, enabling the study of tumor identity for personalized medicine. Leveraging our large PDX collection models which are genomically and phenotypically annotated and validated, we have established and characterized a series of PDXO models to be used as scalable and high throughput compatible drug screening platforms. Here we conducted methodical analysis of drug response in paired PDX and PDXO models. In addition, trough deep whole- and phospho-proteomic analysis, we have analyzed and compared the effect of targeted therapies on protein expression and phosphorylation in both PDX and PDXO tumor models. Indeed, one of the most common post-translational modifications that is involved in cell regulation and intracellular signal transduction is reversible protein phosphorylation catalyzed by protein kinases. For this purpose, we have tested a KRAS inhibitor (AMG510), BCR-ABL TKI (Ponatinib) and EGFR TKI (Afatinib) respectively in lung NSCLC model carrying KRAS G12C mutation, colorectal model with RET fusion and Lung NSCLC model with EGFR exon 19 deletion. According to our historical data, a specific relationship between area under the curve value of organoid drug dose response and in vivo tumor growth has been observed, irrespective of the drug treatment. Furthermore, comparison between PDX and PDXO models deploying quantitative proteomic data enabled deep characterization of both global expression and signaling cascades modulated through small molecule inhibitors. Thus, we demonstrate the predictivity of organoid cultures to not only model in vivo drug responses but also to serve as a powerful platform to investigate target identification, mechanism of action and resistance mechanism via deep proteomics analysis. Citation Format: Xiaoxi Xu, Marco Tognetti, Yuehan Feng, Limei Shang, Leilei Chen, Jessie Wang, Roland Bruderer, Ludovic Bourré, Henry Li. Identification of the phosphorylation network in PDX and corresponding organoid (PDXO) models upon targeted therapy treatment using deep phosphoproteomic analysis[MB1] [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3110.
Abstract 1560: Elucidating the differential regulation of novel long non coding RNAs and their mechanism of action in p73 dependent manner
Authors: Chanchal Bareja, Apoorva Uboveja, Daman Saluja
Journal: Cancer Research (2022)

Abstract INTRODUCTION: The p53 tumor suppressor family is classically activated after DNA damage and plays a central role in cell fate decisions. Although, the p53 family activates many of the same genes in response to DNA damage, p73 plays distinct biological functions in development and metastasis. It is likely that p73 activates a unique transcriptional network which is critical for its anti-metastatic and anti-invasive action. Long non-coding RNAs (lncRNAs) are a class of mRNA-like transcripts longer than 200 nucleotides. They lack protein-coding ability and are believed to be involved in various kinds of biological processes. Increasing evidence suggests that lncRNA are frequently aberrantly expressed in cancers. Therefore, the roles of dysregulated functional lncRNA in human malignant tumors have attracted considerable scientific interest. The objective of our study is to find out novel long non-coding RNAs that can act as transcriptional targets of p73 and to delineate their role in p73-mediated anti-metastatic response. METHODS: For this purpose, we performed transcriptome sequencing in HCT116p73wt and HCT116p73KD cells and screened the data for modulation of expression of lncRNAs in differential manner. Quantitative Real Time PCR was further carried out to validate the data obtained after screening RNA seq Data. Promoter analysis was carried out for the identification of p73 binding sites in the selected upregulated or downregulated lncRNAs which was further confirmed by Luciferase reporter, ChIP and site directed mutagenesis assays. RESULTS: About six lncRNAs were observed to be significantly upregulated while four were down-regulated upon knockdown of p73. The promoters of selected lncRNAs were analysed in silico using TF Bind and JASPAR software for p73 binding sites and luciferase reporter assays suggested regulation of lncRNAs by p73. Chromatin immunoprecipitation showed promoter enrichment of the selected lncRNAs. Site directed mutagenesis further confirmed the exact binding sites of p73 onto the promoters of these novel long non coding RNAs. CONCLUSION: Together, our study provides insights into the differential regulation of long non-coding RNAs in p73 dependent manner which further will provide the mechanism of their action at the genome level. Citation Format: Chanchal Bareja, Apoorva Uboveja, Daman Saluja. Elucidating the differential regulation of novel long non coding RNAs and their mechanism of action in p73 dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1560.
Abstract 1728: Single cell RNA-seq analysis reveals a role of pro-inflammatory tumor-associated macrophages in driving prostate cancer progression
Authors: Jimmy L. Zhao, Joseph Chan, Max Land, Perianne Smith, Anuradha Gopalan, Michael Haffner, Dana Pe'er, Charles Sawyers
Journal: Cancer Research (2022)

Abstract Genomic amplification and increased expression of C-MYC are found in high-grade intraepithelial neoplasm (HGPIN) and primary prostate adenocarcinoma. What role C-MYC plays in the initiation and progression of prostate cancer remains unclear. A genetically engineered mouse model with a high level of human C-MYC protein expression under a probasin promoter (Hi-Myc model) was developed that captures prostate cancer progression from hyperplasia at 6-week-old, to HGPIN at 3-6 month-old, and ultimately to invasive adenocarcinoma at 8-month-old. Applying single-cell RNA sequencing (scRNA-seq) technology, we have carefully studied the temporal transcriptional change in MYC-expressing tumor-initiating cells and the tumor-infiltrating immune cells to understand the cell-intrinsic and -extrinsic mechanisms by which C-MYC promotes the transition from HGPIN to invasive prostate cancer. We have identified a particular type of luminal cells, Prom1+ L1 cells, as the likely tumor initiating cells in the Hi-Myc model. The MYC-expressing L1 tumor initiating cells were more abundant and cycling more often in the invasive cancer at 8-month-old, compared to the pre-invasive stage. Interestingly, significant infiltration of novel M1-like tumor-associated macrophages (TAMs) correlated with the histologic tumor progression from HGPIN to invasive cancer. Targeting TAMs with anti-CSF1R antibody delayed prostate cancer progression and invasion, which appears to be independent of CD8 T-cells. Mechanistically, TAMs expressed a high level of IL-1b, which stimulated Hi-Myc prostate cell proliferation in an organoid co-culture system. More importantly, depleting IL-1b with a neutralizing antibody slowed prostate cancer progression in Hi-Myc mice. Lastly, we found that increased macrophage gene expression was associated with higher Gleason scores and worse disease-free survival in a TCGA clinical patient cohort. In summary, we have identified a molecular mechanism involving pro-inflammatory TAMs and IL-1b in driving early prostate cancer progression in a MYC-driven prostate cancer model, opening a potential therapeutic avenue to target TAMs and pro-inflammatory cytokine in preventing early prostate cancer progression. Citation Format: Jimmy L. Zhao, Joseph Chan, Max Land, Perianne Smith, Anuradha Gopalan, Michael Haffner, Dana Pe'er, Charles Sawyers. Single cell RNA-seq analysis reveals a role of pro-inflammatory tumor-associated macrophages in driving prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1728.
Proximal-tubule molecular relay from early Protein diaphanous homolog 1 to late Rho-associated protein kinase 1 regulates kidney function in obesity-induced kidney damage
Authors: Makiko Ida-Naitoh, Hirobumi Tokuyama, Koji Futatsugi, Marie Yasuda, Keika Adachi, Takeshi Kanda, Yoshiyuki Tanabe, Shu Wakino, Hiroshi Itoh
Journal: Kidney International (2022)
Abstract 6207: Ba/F3 kinase mutant cell panel, a powerful cell model for the discovery and development of inhibitors for kinase specific mutation
Authors: Yu Wang, Yao Peng, Yao Tang, Lin Zhou, Jinying Ning, Feng Hao
Journal: Cancer Research (2022)

Abstract Although over 70 protein kinase inhibitors have been approved by FDA since 2001, the protein kinase is still the hot target class of molecularly targeted cancer therapy because of the discovery of new driver kinase fusion mutation and a large number of secondary kinase mutations after the inhibitor treatment in cancer patients with the sequencing technology advancement, the need for new generation specific small molecule kinase inhibitors is still unmet, and it urge the industry to development more accurate, efficient kinase cellular assay models.Ba/F3 line is a popular cell model because many protein kinases and their mutants can transform the Ba/F3 cells to be growth independent of exogenous IL-3 supplement, while their inhibitors can antagonize these effects. Our group have generated a large of cell line panel with over 300 different well validated (sequencing, Western Blot and inhibitor test) Ba/F3 kinase cell lines for kinase inhibitor screening and development, covering several hot kinases, such as EGFR, EML-ALK, FLT3, NTRK, ROS1, HER, BCR-ABL, RET, FGFR1, FGFR2, FGFR3, FGFR4, KRAS, cMET, et al. Except used in in vitro high-throughput compound screening, most of the transformed Ba/F3 lines can grow well in immune-deficient mice and were also used to evaluate the efficacy of drug candidate and its downstream signaling in vivo. Our data indicate that our Ba/F3 cell line panel is a powerful cell model for new kinase inhibitor discovery and development. Citation Format: Yu Wang, Yao Peng, Yao Tang, Lin Zhou, Jinying Ning, Feng Hao. Ba/F3 kinase mutant cell panel, a powerful cell model for the discovery and development of inhibitors for kinase specific mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6207.
Abstract 5371: Repurposing erbb2 (HER2/neu) as a neoantigen target for neu-negative tumors using a novel erbb2-encoding lentivirus
Authors: Emmanuel M. Gabriel, Brian Necela, Deborah Bahr, Jamie Kaplan, Kristopher Attwood, Keith Knutson
Journal: Cancer Research (2022)

Abstract INTRODUCTION: HER2/neu is a potent biomarker for which anti-HER2/neu antibodies offer significant responses. However, many cancers, such as melanoma, have less than 5% expression of HER2/neu. The purpose of this study was to determine whether induced expression of erbb2 (mouse HER2/neu analogue) could function as a neoantigen target for anti-erbb2 antibody. METHODS: RT-PCR was used to construct a rat erbb2-encoding vector using the live, non-replicating lentivirus pLenti6.3. erbb2-encoding pLenti6.3 was transfected in vitro into the B16 mouse melanoma cell line, which has less than 5% endogenous expression of erbb2. The generated erbb2+ B16 cell line was designated B16/neu. Anti-erbb2 antibody (7.16.4) was used to treat C57Bl/6 male and female mice bearing B16/neu (200 ug intraperitoneally three times per week for 3 weeks). To confirm activity of 7.16.4, this antibody (100 ug per T75 flask) was co-cultured with B16/neu in vitro, and cell growth/confluence was measured. RESULTS: The novel B16/neu cell line expressed approximately 50% erbb2 in vitro on flow cytometry analysis, compared to 2% errb2 expression in naïve B16. Erbb2/neu expression was confirmed on fluorescent Western blot. Anti-erbb2 antibody (7.16.4) slowed the growth of B16/neu in vitro, confirming the suppressive effects of 7.16.4. In B16/neu-bearing mice, 7.16.4 resulted in effective control of tumor growth and a complete tumor response rate of 35.7%, (5/14 mice) compared to placebo controls (p &amp;lt; 0.01). Interestingly, B16/neu tumors demonstrated slower growth kinetics compared to naïve B16 tumors (p = 0.013), suggesting immune recognition of erbb2 in naïve C57Bl/6 mice as a neoantigen target. No adverse reactions were observed with 7.16.4. In vivo inoculation of erbb2-encoding pLenti6.3 in naïve B16 tumors and treatment of in vivo transfected B16/neu tumors with 7.16.4 comprise ongoing experiments. CONCLUSIONS: erbb2 expression on B16 melanoma was successfully achieved using a novel erbb2-encoding lentivirus. Induced erbb2 served as a neoantigen target for anti-erbb2 antibody. This preclinical study provides translational evidence that induced HER2/neu expression may be utilized to repurpose anti-HER2 antibodies for human malignancies that do not normally express high levels of HER2/neu. Citation Format: Emmanuel M. Gabriel, Brian Necela, Deborah Bahr, Jamie Kaplan, Kristopher Attwood, Keith Knutson. Repurposing erbb2 (HER2/neu) as a neoantigen target for neu-negative tumors using a novel erbb2-encoding lentivirus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5371.
Abstract 950: Role of epithelial-mesenchymal plasticity in immune remodeling during metastasis
Authors: Tanvi H. Visal
Journal: Cancer Research (2022)

Abstract Introduction: Breast cancer is the most prevalent type of cancer in women, accounting for 12% of all annual cancer cases worldwide with most deaths attributed to metastasis. It displays both inter- and intra-tumoral heterogeneity which is linked to epithelial-mesenchymal transition (EMT). This program involves the acquisition of a mesenchymal-like phenotype allowing cells to disseminate from the primary tumor and metastasize. However, recent studies show that tumor cells do not need to undergo complete EMT to gain invasive potential; instead, co-expression of both epithelial and mesenchymal markers is critical for metastasis. Such tumor cells are thought to display epithelial-mesenchymal plasticity (EMP) which bestows them with enhanced fitness and flexibility to fulfill diverse requirements of the metastatic cascade. Additionally, hybrid EM phenotype has been linked to immunesuppression but has been understudied due to lack to suitable models with intact immune system. Thus, this necessitates the mechanistic dissection of tumor immune microenvironment (TIME) in models with EM plasticity. To characterize the contribution of EMP to metastasis, we utilized syngeneic mouse mammary tumor cell lines, which are hybrid EM and investigated their proteomic and cytokine profile and identified several novel cytokines. Methods: Reverse Phase Protein Array (RPPA) was performed to determine the proteomic profile of tumors with EM plasticity. In addition, Luminex assay was performed to assess the cytokine/chemokine profile in above tumor models. Results: The RPPA involved a panel of 450 antibodies and showed that tumors with EM plasticity were enriched in specific immunesuppressive proteins. At the same time, Luminex analysis was suggestive of recruitment of tumor-associated macrophages (TAMs) in models with EM plasticity. Additionally, cells with EM plasticity showed the ability to induce tumor-promoting/M2-like macrophages (in vitro). Conclusions: Our data indicates that cells/tumors with EM plasticity show differential protein expression than E and M counterparts and are enriched in specific immunesuppressive proteins. Moreover, such cells have immune networks (cytokines/chemokines) that promote recruitment of TAMs - the largest myeloid infiltrate in the microenvironment of solid tumors. Thus, our study invites more attention to investigate the mechanisms of immunesuppression and metastasis in tumors with EM plasticity. Citation Format: Tanvi H. Visal. Role of epithelial-mesenchymal plasticity in immune remodeling during metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 950.
Abstract 514: Correlation of sTNFR2 elevation and disease progression in cutaneous T cell lymphomas
Authors: Amanda Lee, Youn Kim, Michael Khodadoust, Denise L. Faustman
Journal: Cancer Research (2022)

Abstract Tumor necrosis factor receptor 2 (TNFR2), a membrane receptor that is a part of the tumor necrosis factor (TNF) superfamily and one of two receptors that can bind to TNF-α, has been emerging in recent years as a promising cancer immunotherapy target. TNFR2 is commonly overexpressed in cancer cells and in the tumor microenvironment. It is also a key receptor in immune evasion, due to its abundance on the most immunosuppressive subset of Treg cells (CD4+Foxp3+), as well as its role in driving proliferation of regulatory T cells (Tregs) and tumor cells via activation of the nuclear factor kappa B (NF-κB) pathway. In environments with high cell proliferation and high surface densities, TNFR2 can be cleaved and shed as serum soluble TNFR2 (sTNFR2). In human cancers, high sTNFR2 has recently been associated with poor prognostic outcomes in colon cancer, esophageal cancer, endometrial cancer and non-Hodgkin’s lymphomas. Elevated sTNFR2 is also potentially associated with poor prognostic outcomes in cutaneous T cell lymphomas (CTCLs), a diverse group of lymphomas primarily composed of mycosis fungoides (MF) and Sézary syndrome (SS), with symptoms that primarily manifest in the skin. Given sTNFR2’s accessibility in serum and association with cancer prognosis, we investigated its role as a potential biomarker for MF and SS prognosis. We also evaluated whether the CTCL tumor type is mechanistically being driven by very suppressive Tregs and tumor cells with this oncogene. In our study, we measured baseline sTNFR2 levels from 31 serum samples across different cancer stages (Stage I-IV) of MF and SS in either treatment-naïve subjects or subjects free of any treatments for ≥3 months. Our initial data shows that sTNFR2 values correlate with levels of blood disease and increase as the cancer advances. These findings strengthen the possibility of using sTNFR2 as a biomarker in MF and SS and also support the possible mechanistic role of TNFR2 in disease pathogenesis. Analysis of the same serum samples for sTNFR1, a non-specific marker of inflammation and renal failure, confirm that the increases are exclusive to sTNFR2 and can indeed be attributed to MF and SS, rather than to non-specific inflammation. Further studies following these patients’ responses to their treatment plans (i.e., mogamulizumab, romidepsin) will help elucidate the potency of sTNFR2 in predicting response to treatment and cancer burden. Citation Format: Amanda Lee, Youn Kim, Michael Khodadoust, Denise L. Faustman. Correlation of sTNFR2 elevation and disease progression in cutaneous T cell lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 514.